Self-renewal and differentiation are fundamental characteristics of all stem/progenitor cells. During mammalian development stem/progenitor cells use cell polarity mechanisms to divide asymmetrically to renew themselves and generate daughters that stop proliferation and differentiate. Similar mechanisms are used for self-renewal and differentiation of adult stem cells. Failure of asymmetric cell divisions in stem cells may result in inability to withdraw from cell cycle, perturbations of normal brain development and cancer. Alternatively, failure of stem cell self-renewal can cause depletion of stem cells, decline in tissue regenerative potential and premature aging. The molecular mechanisms governing cell polarity and asymmetric cell divisions of mammalian stem/progenitor cells and their role in aging and cancer are still poorly understood. This proposal focuses on cell polarity proteins, Lethal giant larvae 1 and 2 (Lgl1 and Lgl2), which represent the mammalian orthologs of Drosophila neoplastic tumor-suppressor protein Lgl. We have evidence that Lgl1 is necessary for regulation of asymmetric cell division of neural progenitor cells during early neurogenesis and loss of Lgl1 results in abnormal accumulation of progenitors that fail to withdraw from the cell cycle. Neonatal death of Lgl1-/- mice precluded us from the analysis of potential tumor- suppressor role of Lgls in adult animals and their role in self-renewal of adult stem cells. In this proposal we will use a variety of conditional gene knockout and biochemical approaches to investigate the potential in vivo role and significance of the entire Lgl gene family and molecular mechanisms responsible for function of Lgl proteins in regulation of stem/progenitor cell self-renewal and differentiation. These studies will help to extend our knowledge of the mechanisms of self-renewal and differentiation of mammalian stem/progenitor cells. This information will be useful for future development of efficient regenerative, anti-aging and anti-cancer therapies. PUBLIC HEALTH RELEVANCE: Studies described in this proposal will help to understand how stem cells are maintained in the adult mammalian organism and whether abnormalities with stem cells are responsible for cancer. Knowledge obtained during this study will help to develop new therapies for treatment of tissue injury, degenerative diseases and cancer.